Title: Bridging What is Known and What is Not Known FDA Perspective and Response
1Bridging What is Known and What is Not
KnownFDA Perspective and Response
- Janet Woodcock, M.D.
- Director, Center for Drug Evaluation and Research
- Food and Drug Administration
2Topics
- Role of FDA Drug Regulation
- Estrogen and progestin drugs approved for
menopausal conditions - Impact of WHI Results
- Question of generalizability of findings
- Implications of WHI for Risk Management
- Conclusions
3FDA Drug Regulation
- Applies to pharmaceuticals Demonstration of
Safety and Effectiveness - Dietary Supplements regulated under a different
law - no FDA review of clinical data
4Requirements for Pharmaceuticals Effectiveness
- Demonstrated in adequate and well controlled
trials - Applies only to indications in label
- For chronic administration demonstration of
long-term effectiveness not required - Advertising limited to approved indications and
must conform to the data
5Requirements for Pharmaceuticals Safety
- No drug is absolutely safe
- Safety benefits exceed risks for defined
population and use - Longer term risks difficult to assess
- Challenges of randomized trials
- Positive benefit-risk may not apply to
off-label use
6Estrogen and Progestin Drugs Approved for
Menopausal Conditions
- Five approved combination products four oral,
one transdermal patch - Fifteen estrogen products oral, transdermal
patches, injections, topical gel, vaginal ring - Six progestins oral, injection and gel
7Approved Indications for Menopausal Conditions
- Vasomotor symptoms
- Vulvar vaginal atrophy
- Prevention of osteoporosis
- Not approved for
- Prevention of cardiovascular disease
- Hormone replacement
8Treatment of Vasomotor Symptoms Current
Standards
- Trial design 3 month placebo-controlled,
multiple dose, 60-100 subjects/group - Endpoints
- Clinically statistically significant reduction
in frequency and severity of hot flashes weeks
4-12.
9Treatment of Vulvar Vaginal Atrophy
- Trial design 3 month placebo- controlled,
multiple dose, - 60-100 subjects/group
- Endpoints
- Statistically significant at 12 weeks
- Symptom reduction
- Lowering of vaginal pH
- Improvement in maturation index
10Prevention of Osteoporosis
- Trial design 2 yr placebo controlled,
typically 150-300 subjects - Endpoints
- Lumbar spine bone mineral density
11Estrogens Progestins, and Estrogens, Approved
for Prevention of Postmenopausal Osteoporsis
- Product Active Ingredients
- Activella estradiol/norethindrone
- Femhrt ethinyl estradiol/norethindrone
- Ortho-Prefest estradiol/norgestimate
- Estrace estradiol
- Ogen estropipate
- Ortho-est estropipate
- Vivelle (patch) estradiol
- Climara (patch) estradiol
12FDA- approved Non-estrogens for Treatment and
Prevention of Premenopausal Osteoporosis
- Drug Class
- Alendronate Bisphosphonate
- Risedronate Bisphosphonate
- Raloxifene SERM
13Pre-WHI Safety Labeling Prempro
- Warnings section known risks discussed
- Induction of malignant neoplasms, including
reports of moderately increased risk of breast
cancer - Thromboembolic disorders including venous TE
- Precautions Section A relationship between
estrogen.. therapy and reduction of
cardiovascular disease has not been proven
14Impact of WHI Results on Menopausal Drug
Development
- FDA considering public Advisory Committee Meeting
- Impact on current labels
- Trial length for safety data
- Trial size for population experience
- Generalizability of WHI results
15Generalizability of WHI Results What do results
with Prempro imply for other estrogen/progestin
drugs
- Two issues
- Composition
- Dose
16Composition
- Prempro .625 mg conjugated equine estrogens
(CEE) - 2.5 or 5.0 mg medroxyprogesterone acetate
- CEE Complex mixture
17Composition of Premarin Component of Prempro
- Derived from pregnant mares urine
- 0.625 mg is a convention does not quantitate
amounts - Multiple estrogen components pharmacologic
characteristics of separate components not well
characterized
18Sodium Estrogen Sulfate mg/.625 mg tablet
- Estrone .370
- Equilin .168
- 17-?- Dihydroequilin .102
- 17-?- Estradiol .027
- 17-?- Dihydroequilin .011
- 17-?- Dihydroequilenin .011
- 17-?- Dihydroequilenin .015
- 17-?- Estradiol .005
8,9-Dehydroestrone .026 Equilenin .015
19Composition Estrogens
- Premarin contains unique equine estrogens in
addition to estrone/estradiol - Equine estrogens may have different
pharmacodynamic properties - Only two other approved products contain equine
estrogens
20Composition Progestins
- Premarin also contains progestins - activity not
known - Medroxyprogesterone acetate not a component of
any other combination product
21Dosage
- Original estrogenic potency assignment based on a
rat bioassay - Effects on rat do not parallel human
- Pharmacokinetic difference among estrogens
22Pharmacokinetic Studies
- Estrogen Estrone Equilin
8,9-DHE - Measured dose
- or AUC
- mg per 1.25mg dose .740 .336 .052
- ng. Hr/ml AUC
- Total plasma 94.2 43.1 13.6
- Ketone
- Unconj. plasma 4.08 1.2 .07
- Ketone
- Total plasma 8.57 10.6 6.62
- 17 ? diol
- Unconj. Plasma 0.66 1.06 0.33
- 17 ? diol
23- Synthetic Generic Conjugated Estrogens
- Website
- http//www.fda.gov/cder/cepage.htm
24Generalizability Dose
- Drug toxicities are frequently dose related
- WHI toxicity findings are generally congruent
with potential class effects of estrogen and
progestin - Not possible to extrapolate dose/toxicity
findings directly to other related products
25Risk Management Implications of WHI findings
- Prevention indications Need to be assured of
positive benefit/risk analysis in people without
symptoms - Minimizing risk Data questions
- Relationship of dose or duration to toxicity
- Relationship of route of administration to
toxicity
26Risk Management Implications of WHI findings
- Maximizing benefit
- Women with more severe menopausal symptoms
- Women at higher risk of osteoporosis
27Risk Management Information Dissemination
- Informative product labels
- Patient education efforts by companies
- Responsible advertising promotion
28Summary
- WHI results provide important additional risk
information on estrogen/progestin combinations - Quantitative extrapolation to similar products
not possible - There are implications for new drug development
in this area - It is imperative that accurate information be
available to prescribers and patients